The dementia of Alzheimer's disease (AD) correlates with the deposit of amyloid plaques in brain, and there is an urgent need for new drugs that disaggregate the plaque in brain. The most potent plaque disaggregation drugs are anti-amyloid antibodies (AAAs). However, the AAA must physically contact the plaque to cause disaggregation, and the plaque resides in brain behind the blood-brain barrier (BBB). AAAs, like other large molecule drugs, do not cross the BBB in the absence of BBB disruption. A side effect of AAA therapy in either transgenic mouse models, or in humans with AD, is a dramatic increase in the plasma concentration of Abeta amyloid peptides, and this is associated with cerebral micro-hemorrhage in mice and vasogenic brain edema in humans. What is needed is a new generation of AAAs that both penetrate the BBB without barrier disruption, and do not cause elevations in plasma amyloid peptides or brain edema or BBB disruption. In the present work, an AAA is re-engineered to cross the mouse BBB via receptor-mediated transport on the transferrin receptor (TfR). A single chain Fv (ScFv) form of the AAA is engineered, and the ScFv is fused to the carboxyl terminus of the heavy chain of a genetically engineered chimeric monoclonal antibody (MAb) against the mouse TfR, and this fusion protein is designated cTfRMAb-ScFv. The fusion protein was administered chronically to double transgenic AD mice and treatment caused a 40% decrease in brain Ab1-42 with no increase in plasma Ab1-42 and no cerebral micro-hemorrhage. In the proposed work, a dose response study will be performed in both the double transgenic and the triple transgenic mouse models of AD. In addition, AD transgenic mice will be treated with dual biologic therapy with the brain penetrating AAA and a brain penetrating tumor necrosis factor (TNF)-alpha inhibitor. The AAA therapeutic accelerates the disaggregation of amyloid plaque in brain, while the brain penetrating TNF-inhibitor diminishes the production of amyloid plaque in brain of AD transgenic mouse models. PUBLIC HEALTH RELEVANCE: The dementia of Alzheimer's disease correlates with the deposition of amyloid plaques in brain, and there is an urgent need for new drugs that disaggregate the plaque in brain. The most potent plaque disaggregation drugs are anti-amyloid antibodies (AAAs). In the present work, an AAA is re- engineered to cross the blood-brain barrier (BBB) via receptor-mediated transport on the transferrin receptor. The goal of this drug development program is the engineering of an AAA that is brain penetrating in the absence of BBB disruption, and reduces brain amyloid plaque without causing elevations in plasma amyloid peptides or cerebral micro-hemorrhage.